FEB 21, 2018 12:00 PM PST

Allosteric Modulation of Metabotropic Glutamate Receptors for the Treatment of Neurodevelopmental Disorders

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  • Professor of Pharmacology, Director of Molecular Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery
      Colleen Niswender is a Professor of Pharmacology at Vanderbilt University and the Director of Molecular Pharmacology for the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD). During her graduate training and initial postdoctoral studies, she worked to elucidate the molecular mechanisms regulating the RNA editing of AMPA and serotonin receptors. She then pursued postdoctoral studies focused on the genetic regulation of Protein Kinase A using recombinant mice at the University of Washington. Her work at the VCNDD involves assay development, high throughput screening and characterization of novel G protein-coupled receptor allosteric ligands both in vitro and in vivo. She has been involved in multiple small molecule discovery projects to search for and characterize novel allosteric modulators of various metabotropic glutamate (mGlu) and muscarinic receptors. This work has resulted in the progression of an M1 muscarinic receptor positive allosteric modulator, discovered at Vanderbilt, through Investigational New Drug Application studies and into clinical development for the treatment of cognitive deficits in Alzheimer's disease and schizophrenia. During the past five years, Dr. Niswender has established a new research program focused on the therapeutic potential of mGlu and muscarinic receptor allosteric modulators for the treatment of various neurodevelopmental disorders, including Rett syndrome, MECP2 Duplication syndrome, and Neurofibromatosis Type 1.


    Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the Methyl CpG Binding Protein 2 (MECP2) gene. In mouse models of RTT, deficits in long-term potentiation (LTP) at Schaffer collateral (SC)-CA1 synapses in the hippocampus, as well as impairments in learning and memory. The metabotropic glutamate receptor 7 (mGlu7) is the primary mGlu receptor expressed presynaptically at SC-CA1 synapses in adult mice, and is required for the induction of LTP. By examining autopsy samples from human RTT patients, we have found an approximately 70 percent reduction in mGlu7 protein expression in both cortex and cerebellum. mGlu7 levels are also reduced in RTT model mice and positive allosteric modulation of mGlu7 activity restores LTP and improves contextual fear learning and social phenotypes. Furthermore, mGlu7 potentiation decreases apneas in RTT model mice, suggesting that mGlu7 may represent a therapeutic target for multiple aspects of the RTT phenotype.

    While RTT is caused by loss-of-function mutations in MECP2, MECP2 Duplication syndrome (MDS) is another severe neurodevelopmental disorder resulting from overexpression of the MeCP2 protein. Mouse models of RTT and MDS show opposing changes in presynaptic activity at SC-CA1 synapses, and we hypothesized that genetic reduction of mGlu7 or an mGlu7 negative allosteric modulator (NAM) might correct deficits in MDS-model mice. Surprisingly, cognitive and anxiety phenotypes found in MDS animals were not impacted by reducing mGlu7 expression or by administration of an mGlu7 NAM. In contrast, a PAM unexpectedly corrected these deficits, suggesting that shared underlying circuitry changes between RTT and MDS may explain these findings. Finally, this presentation will touch upon primary GRM7 mutations and SNPs that are now being correlated with severe neurodevelopmental disorders in clinical populations.

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